tbuckley/cabot-search huggingface dataset:
Long-term survivors (LTSs) population of metastatic colorectal cancer (mCRC): A Northern Italian comprehensive cancer center experience.
Authors: Angela Damato, Martina Rotolo, Eleonora Borghi, Francesco Caputo, Francesco Iachetta, Michele Panebianco, Silvia Fanello, Mattia Lombardi, Erika Gervasi, Mario Larocca, Carmine Pinto
Journal: Journal of Clinical Oncology (2023)

e15590 Background: mCRC patients (pts) have a median survival of 13-24 months with a 5-year survival rate of about 1%. LTSs are defined as pts with survival greater than or equal to 36 months after diagnosis of mCRC. Mutational status, new treatments, and surgery resection advances led to improved survival outcomes. Methods: This is a single-center retrospective analysis of 106 consecutive CRC pts with synchronous or metachronous metastases diagnosed from the AUSL-IRCCS of Reggio Emilia Comprehensive Cancer Center between January 1 st , 2017, and November 30, 2019. Clinical and pathological characteristics of pts were obtained from clinical records. Long-term survivors were defined as pts with survival &gt; 36 months. Results: Out of 106 mCRC, 33 (31.1%) were LTSs with a median survival of 53 months (range, 36-129 months). At the data cut-off of November 30, 2022, 24 (72.7%) were still alive. Among all, 18 (54.5%) were men, the median age was 65 years (47-83), and 14 (42.4%) had a right tumor primary site. Synchronous metastases were found in 20 (60.6%), while 13 (39.4%) developed metachronous metastases; the most frequent site of metastases was the liver (63.6%), peritoneum and lymph nodes (21.2%), respectively. Surgical resections and systemic treatment regimens based on fluorouracil, oxaliplatin, and/or irinotecan, cetuximab, bevacizumab, TAS-102, regorafenib, and others are listed in Table 1. Regarding biological status, 28 (84.8%) had an MSS, 18 (54.5%) RAS wild type, and 3 (9.1%) BRAF V600E mutated of which 2 (66.7%) underwent surgical resection of primary tumor and metastases, receiving up to 2 lines of systemic treatments. Conclusions: This study confirms that long-term survivors of mCRC pts are the results of intrinsic tumor biology, appropriate treatment timing including surgery, and the available pharmacological opportunities beyond chemotherapy. Further analysis including the role of liquid biopsy is under investigation to identify prognostic and predictive biomarkers in order to improve survival outcomes. [Table: see text]
AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer.
Authors: Eileen Mary O'Reilly, Zev A. Wainberg, Colin D. Weekes, Muhammad Furqan, Pashtoon Murtaza Kasi, Craig E. Devoe, Alexis Diane Leal, Vincent Chung, James Perry, Lochana Seenappa, Lisa McNeil, Esther Welkowsky, Peter DeMuth, Christopher M. Haqq, Shubham Pant
Journal: Journal of Clinical Oncology (2023)

2528 Background: RAS mutations occur in 25% of solid tumors with G12D being the most frequent variant. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Preclinical amphiphile data (relative to non-amphiphile controls) showed increased immunogenicity, tumor clearance and survival in mouse models. Methods: This first-in-human multicenter phase I trial assessed safety, immunogenicity and antitumor activity using a novel adjuvant trial design in patients (pts) with minimal residual disease (MRD) following standard locoregional treatment. Eligibility: elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker elevation (CA19-9/CEA), and KRAS/NRAS mutation. In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). Dose escalation based on observed safety in first 28 days. Safety, antitumor activity including biomarker reduction/clearance and relapse free survival using immune Response Evaluation Criteria in Solid Tumors (iRECIST) were assessed. Immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells (T-cell responders = ≥ 2-fold increase over baseline) and by tumor CD3 immunohistochemistry in subset who underwent a biopsy. Results: No dose-limiting toxicities, treatment related SAEs or cytokine release syndrome were observed, and no maximum tolerated dose was identified. Safety: all grade 1, fatigue (19%), headache (19%), and injection site reaction (9.5%). Biomarker reduction was observed in 15/19 (79%) and in 5/5 at highest doses; clearance of MRD was observed in 4/19 (21% - n=2 pancreas, n=2 colorectal). Polyfunctional mKRAS-specific T cell responses observed in 80% of pts (n=12/15), with both CD8+ and CD4+ T cell responses for most, and CD3+ T cells observed on biopsies. The recommended phase 2 dose (RP2D) is 10.0 mg Amph-CpG-7909. Conclusions: ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017 . [Table: see text]
Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status.
Authors: David Olmos, David Lorente, Daniel Alameda, Carlo Cattrini, Nuria Romero-Laorden, Rebeca Lozano, Pedro P. Lopez-Casas, Camille Capone, Anne Marie Vanden Broecke, Marco Trevisan, Suzy Van Sanden, Alexandra Jürgens, Bernardo Herrera-Imbroda, Elena Castro
Journal: Journal of Clinical Oncology (2023)

5003 Background: Understanding of the association between HRR mutations and outcomes in mCRPC pts is limited. This analysis investigated the prevalence and outcomes of pts with/out HRR mutations (somatic and/or germline), stratified as BRCA, non-BRCA, or HRR non-BRCA, who initiated 1L mCRPC treatment with novel hormonal therapy (NHT) or taxane. Methods: Eligible pts from PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), and PROSABI (NCT02787837) studies underwent paired somatic/germline DNA analyses using a custom NGS panel that included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B, and RAD54L. Those with pathogenic (likely) mutations in ≥1 allele of ≥1 gene were considered deficient (HRR). rPFS, PFS2, and OS were reported for BRCA, non-BRCA, and HRR non-BRCA subgroups; associations between mutations and outcomes were assessed using inverse probability weighted Cox models, which balanced the baseline (BL) characteristics between subgroups. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p values are presented. Results: Of 729 pts, 223 (30.6%) were HRR, including 96 (13.2%) BRCA. 60.4% of pts were treated with NHT and 39.6% with taxane in 1L; 80.7% received at least second-line treatment. Median age at BL was 72.2 years, 63.5% had Gleason &gt;7, 53.1% had ECOG ≥1, and 13.3% presented with visceral metastases. BL characteristics after adjustment were similar (standard mean difference: &lt;0.1 in HRR and maximum 0.11 for all pts). BRCA pts had significantly worse rPFS, PFS2, and OS than non-BRCA pts; BRCA pts also had significantly worse PFS2 and OS than HRR non-BRCA pts. There were no significant differences between the outcomes of somatic and germline BRCA pts. Conclusions: BRCA pts, regardless of somatic/germline origin, had significantly worse rPFS, PFS2, and OS than the total non-BRCA population and significantly worse PFS2 and OS than non-BRCA pts in the HRR subgroup. It is crucial to screen early for HRR mutations, particularly in BRCA1/2, to begin timely, targeted mCRPC treatment and improve prognosis.[Table: see text]
Landscape and impact of germline pathogenic variants (PVs) in metastatic hormone sensitive prostate cancer (mHSPC): Ancillary study of E3805 CHAARTED.
Authors: Anis Hamid, Tyler M Chinsky, Matias Vergara, Emily Grist, Gerhardt Attard, Eliezer Mendel Van Allen, Saud Aldubayan, Christopher Sweeney
Journal: Journal of Clinical Oncology (2023)

5082 Background: Enrichment of germline PVs in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence and prognostic/predictive associations of such variants are not well characterized in the mHSPC state, in particular the effect of susceptibility mutations related to DNA damage and repair (DDR) pathways. Methods: We performed whole exome sequencing of germline DNA derived from whole blood available from patients (pts) in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel (ADT+D). After filtering for low coverage, variant annotation and effect prediction, PVs from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic effect of PVs was evaluated within each treatment arm. Endpoints of time to CRPC (ttCRPC), time to clinical progression (ttClinPD), and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models evaluating association of endpoints with biomarkers/arm. Multivariable analysis adjusted for metastatic timing and volume. Results: Of 137 pts, 135 had unique germline exomes that passed downstream analysis. Most pts had synchronous (66.7%) and high-volume (62.2%) disease. This biomarker cohort showed benefit of adding docetaxel to ADT (ttCRPC: HR 0.55, 95% CI 0.37-0.82; OS: HR 0.68, 95% CI 0.44-1.07). In total, 61 PVs were detected; 49 pts (36.3%) harbored at least 1 PV in 41 different genes. The most frequently-mutated gene was BRCA2 (6.67%). In addition, PVs were found in DDR-associated genes including PALB2 (1.48%), CHEK2 (1.48%), BRCA1 (0.74%) and PMS2 (0.74%) for an overall prevalence of 11.1% (15/135). Pts with BRCA2 PV on ADT alone had shorter ttCRPC compared with men without the PV (UVA: HR 2.67, 95% CI 0.93-7.63, log rank p=0.057; MVA: HR 2.59, 95% CI 0.91-7.39, p=0.074). There was no evidence of a difference in the ADT+D arm (UVA: HR 1.00, 95% CI 0.31-3.25, log rank p=0.1). Supportive data was observed for ttClinPD in ADT arm (HR 2.85, 95% CI 1.01-8.08, log rank p=0.04). Metastatic volume and timing were not significantly associated with germline BRCA1/2 or DDR PVs. Conclusions: The prevalence of germline BRCA1/2 and DDR PVs in mHSPC is similar to mCRPC and BRCA2 PV may confer worse outcomes on ADT alone. This supports the need for genetic testing at diagnosis of mHSPC. [Table: see text]
Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Karl Semaan, Talal El Zarif, Renee Maria Saliby, Marc Eid, Eddy Saad, Chris Labaki, Lucia Kwak, Marina D. Kaymakcalan, Sylvan Baca, Stephanie A. Berg, Wanling Xie, Charlene Mantia, Toni K. Choueiri, Bradley Alexander McGregor, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2023)

e16585 Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with &gt; 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]
MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).
Authors: Shilpa Gupta, Karla V. Ballman, Matt D. Galsky, Michael J. Morris, Srikala S. Sridhar, Ronald C. Chen, Timothy An-thy Chan, Yujia Wen, Petros Grivas, Alan Tan, Shiva Baghaie, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2023)

TPS4609 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Clinical trial information: NCT05092958 .
Prospective study of integrating post-radiotherapy [<sup>18</sup>F] fluorodeoxyglucose-positron emission tomography/computed tomography scan and plasma Epstein-Barr virus DNA in surveillance of locoregionally advanced nasopharyngeal carcinoma.
Authors: Lin-Quan Tang, Li-Ting Liu, Zhen-Chong Yang, Jia-Yi Shen, Mei-Juan Luo, Ying-Ying Hu, Zi-Jian Lu, Bei-Bei Xiao, Jin-Hao Yang, Xiao-Fei Lv, Guo-Dong Jia, Shan-Shan Guo, Qiu-Yan Chen, Wei Fan, Hai-Qiang Mai
Journal: Journal of Clinical Oncology (2023)

6072 Background: To evaluate the role of [ 18 F] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan at 12-weeks after the end of Radiotherapy (RT) integrated with plasma EBV DNA in surveillance and standardized implementation of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This prospective study was conducted in patients with stage III-IVa LA-NPC. FDG-PET/CT examination and plasma Epstein-Barr virus (EBV) DNA measurements was performed pretreatment and at 12-weeks after the end RT. The primary study endpoint was the negative predictive value (NPV) and other supporting diagnostic test characteristics of 12-weeks FDG-PET/CT for the surveillance of residual locoregional disease and new distant metastasis. Results: From June 2018 to December 2019, 506 eligible patients were enrolled and entered follow-up (median,45 months). At 12 weeks after the end of RT, there were 22 (4.3%) patients have residual locoregional disease, 30 (5.9%) patients developed distant metastasis and 6 (1.2%) patients presented both residual locoregional disease and distant metastasis. The NPV of 12-weeks FDG-PET/CT for overall residual diseases and distant metastasis was 96.3% (95% confidence interval [CI], 94.0%-97.8%) with sensitivity of 72.4% (95%CI, 58.9%-83.0%), specificity of 93.3% (95%CI, 90.5%-95.4%), positive predictive value (PPV) of 58.3% (95%CI, 46.1%-69.6%) and accuracy of 90.9% (95%CI, 88.4%-93.4%). In EBV DNA-based risk subgroups, the NPV of 12-weeks PDG-PET/CT was 96.8% (95%CI, 94.5%-98.2%) in patients with undetectable 12-weeks plasma EBV DNA and 87.0% (95%CI, 65.3%-96.5%) in patients with detectable 12-weeks plasma EBV DNA. Conclusions: 12-weeks PDG-PET/CT was reliable in the surveillance of LA-NPC and could help optimize the follow-up strategy and provide implications for timely and effective therapeutic regimen, especially for patients in different EBV DNA-based risk groups. Clinical trial information: NCT03601390 .
A retrospective study exploring the safety and efficacy of hepatic arterial infusion chemotherapy and sequential transarterial embolization combined with lenvatinib and tislelizumab in unresectable hepatocellular carcinoma.
Authors: Jian-Hong Zhong, Zu-Shun Chen, Lu-Nan Qi, Zhi-Ming Zhang, Bang-De Xiang, Liang Ma
Journal: Journal of Clinical Oncology (2023)

e16219 Background: Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) and lenvatinib with or without immune checkpoint inhibitors (ICIs) are first-line treatment in unresectable hepatocellular carcinoma (HCC). However, the objective response rate (ORR) under HAIC plus lenvatinib and ICIs is not satisfactory. Hereby, we retrospectively explore the efficacy and safety of the combination therapy of HAIC sequential transarterial embolization (TAE) combined with lenvatinib and tislelizumab as a first-line treatment in patients with unresectable HCC. Methods: A retrospective analysis of related clinical data of 35 unresectable HCC patients who received HAIC-TAE combined with lenvatinib and tislelizumab were performed. All patients received at least once HAIC sequential TAE combined with lenvatinib and tislelizumab. The primary end-point was the progression-free survival (PFS) rate per mRECIST at six months. The secondary endpoints included safety, objective response rate (ORR), overall survival (OS), surgical conversion rate and disease control rate. Results: Thirty-five patients (65.7% with BCLC C stage while 22.9% with BCLC B stage disease) were enrolled. The primary end-point of PFS rate was 77.1% at six months. However, the median overall survival was not reached at February 10, 2023. The ORR per RECIST 1.1 was 36.4%, and per mRECIST was 63.6% after twice HAIC sequential TAE. Progressive disease was found in 1 patient in each course of HAIC sequential TAE. Eight patients (22.9%) with 12 tumors received curative hepatic resection. Among these eight patients, two patients (25%) and five tumors (41.7%) were with pathological complete response. Six patients (75%) and ten tumors (83.3%) were with tumor necrosis more than 90%. The rate of tumor necrosis more than 50% was 100%. Four patients with partial response received radiotherapy (n=3) or radiofrequency ablation (n=1). The most common adverse events were elevation of alanine aminotransferase, fever and abdominal pain, and no treatment-related death was reported. Conclusions: FOLFOX-HAIC sequential TAE combined with lenvatinib and tislelizumab showed safe and encouraging antitumor activity for unresectable HCC. Based on the data from this study, a prospective, single-arm Phase II trial is planned. Clinical trial information: NCT05532319 .